Skin is a large and complex body organ. In humans and many animals, it can comprise from about 15 to 20% of the entire body weight. It serves as a protective barrier to environmental toxins and assaults. Conditions on the skin, or conditions in the body, can cause inflammation or irritation, or both, of the skin. Pain is often associated with such conditions. Such conditions may originate from a variety of sources, including, but not limited to, insect bites and stings, e.g., mosquito bites and bee stings, skin irritants, e.g., poison ivy, or conditions of the skin or body, e.g., eczema or arthritis. There are several biological pathways that may contribute to skin inflammation. For example, one immune response of assaulted tissue is histamine release, predominantly by basophilic cells. Another pathway that may contribute to skin inflammation is release of enzymes such as, for example, cyclooxygenase-2 (also referred to as COX-2), an enzyme known to promote inflammation and pain, or phospholipase-2 (PLA-2) by cells and tissue subjected to immune assaults.
For example, the skin contains nerves and highly specific sensory organs that are specialized and disposed so as to differentiate the stimuli leading to such distinct sensations as heat, cold, pressure, pain, itch and the like. In addition to normal sensory stimuli, nerves in the skin are also responsive to native or foreign chemicals such as proteases, prostaglandins, complement-system molecules, allergens, mitogens and the like which may be presented due to tissue injury or environmental exposure. Agents which are effective to combat one source of sensory stimulus—for example steroidal agents to treat skin inflammation—are ineffective against other sensory stimuli such as pressure, heat, or the transitory sting or itch caused by an applied skin care product. Conversely, local anesthetic agents which are effective to depress all sensory or even motor activity in a treated region are not desirable if only a single sensation—for example a transitory sting or itch—is sought to be eliminated. To complicate the situation, the structural matrix of the skin affords a “barrier function” which tends to exclude or inhibit the entry of foreign material, including potentially therapeutic agents.
Typical compositions suitable for topical application to the skin often contain a medicament such as hydrocortisone as their essential active ingredient. Other compositions, such as described, for example in U.S. Pat. No. 8,147,855, granted Apr. 3, 2012, disclose methods for inhibiting sensory responses in the skin such as pain and itch using topical formulations containing aqueous-soluble divalent strontium cation in a suitable topical keratinized skin formulation vehicle. Such a composition may, for example, contain an astringent such as aluminum acetate in a suitable concentration, e.g., 0.2 wt %, and other suitable inactive ingredients, e.g., butylene glycol, caprylyl glycol, dehydroacetic acid, glycine, malic acid, phenoxyethanol, water, and , xanthan gum, and further optionally including other ingredients such as strontium chloride hexahydrate. Other compositions may include an abrasive component such as, for example, ground walnut shells. While these products may be at least partially effective in alleviating symptoms, e.g., itch, they may not be effective in managing the source of the condition, e.g., removal of histamine or enzyme from the affected area of the skin.
Another composition indicated for management of moderate pruritus is one which contains doxepin hydrochloride and has been available, for example, under the trademark ZONALONTM (doxepin hydrochloride) cream, 5%, from Fougera Pharmaceuticals, Inc. In its package insert, under the section entitled “CLINICAL PHARMACOLOGY”, it is stated that “Although dopxepin HCL does have H1 and H2 histamine receptor blocking actions, the exact mechanism by which doxepin exerts its antipruritic effect is unknown.”.
Accordingly, new methods and compositions are desired for treating conditions on the skin, e.g., itch, insect bite or sting, inflammation, pain or irritation. Further, new methods and compositions are desired for treating conditions on the skin that can remove or eliminate biologic compounds, e.g., histamine or an enzyme, that may contribute to the discomfort associated with the particular condition.